The subject of the present invention is a novel process for preparing compounds of the diaminophenothiazinium type, in particular a process for purifying these compounds. It relates in particular to methylene blue, and the subject thereof is also the products resulting from this process, the degree of purity of which is higher than those known in the prior art. A subject of the present invention is also the use of these compounds for the preparation of medicaments.
Methylthioninium chloride, also known as methylene blue or 3,7-bis(dimethylamino)phenothiazin-5-ylium chloride, is an organic compound corresponding to the formula below:

This compound has for a long time been used as a redox indicator and dye, as an optical developer in biophysical systems, in nanoporous materials as a separating material, and in photoelectrochromic imaging. It is also known for its uses as an antiseptic, antiinfective, as an antidote and as a diagnostic agent. It finds uses in particular in gynecology, neonatology, cancerology, oncology, urology, ophthalmology and gastroenterology. New uses in the therapeutic field are in the process of being developed, such as the reduction of pathogenic contaminants in the blood (GB2373787), or the prevention or inhibition of an exaggerated hemodynamic reaction (WO03/082296).
Many methods of synthesis have been described for this compound, since the oldest in 1877 (German patent No. 1886). All these methods have in common the fact of using metal compounds in at least one synthetic step:
Patent DE-1886 describes a process in which oxidative coupling of N,N-dimethyl-1,4-diaminobenzene is carried out with H2S and FeCl3.
Fiez David et al., “Fundamental Processes of Dye Chemistry”, 1949, Interscience, 308-314 describes a process in which the thiazine ring is formed by treatment with manganese dioxide or with copper sulfate. This process also comprises a treatment with zinc chloride, with sodium dichromate and with aluminum thiosulfate.
Document WO 2005/054217 describes methylene blue derivatives and a process for the preparation thereof. The method for preparing these compounds uses phenothiazine as starting product. Now, all the known methods for preparing phenothiazine call for metal reactants of which the metal atoms chelate the phenothiazine at the end of the synthesis. The products obtained by means of this process are therefore naturally contaminated with metal residues, in addition to the usual organic contaminants such as azure B.
Document WO 2006/032879 describes a process for preparing methylene blue which comprises a reduction step with iron, an oxidation step with sodium dichromate and an oxidation step with copper sulfate.
These processes require tedious and expensive purifications to be carried out in order to reduce the impurities, in particular the metal impurities of methylene blue. Despite the subsequent purification steps, these various processes inevitably produce a methylene blue comprising many metal impurities and also organic impurities, in particular azure B, azure C and azure A.
Document WO 2006/032879 asserts that it is possible to achieve a level of metal impurities representing 10% of the maximum threshold fixed by the European Pharmacopeia, but, according to the examples, it is noted that this level is not obtained simultaneously for all metals, and the results of the purification steps are not always reproducible. A detailed analysis of the metal contents of various commercially available methylene blues is illustrated in this document.
The European Pharmacopeia was recently amended (April 2006) in terms of an increase in the tolerance thresholds for metal impurities since no producer of methylene blue was able to produce, and even less to produce in an industrial amount, a methylene blue of a quality meeting its previous requirements.